Samuel C. Risch

Cholinergic challenges in affective illness: behavioral and neuroendocrine correlates.

The cholinergic-adrenergic balance hypothesis of affective disorders suggests that, in the areas of the brain that regulate mood, depression may represent a relative predominance of central cholinergic tone over adrenergic tone and that mania may represent the converse. Currently, converging lines of investigation from a number of independent groups suggest that affective disorder patients may have a central cholinergic receptor hypersensitivity that induces a vulnerability to affective and neuroendocrine disturbances. This article reviews the evidence for cholinergic mechanisms in the regulation of affective state and describes current research strategies using centrally active cholinomimetic agents to explore disturbances in affective disorder subjects.

Differential time course of cytochrome P450 2D6 enzyme inhibition by fluoxetine, sertraline, and paroxetine in healthy volunteers.

The selective serotonin reuptake inhibitors (SSRIs) paroxetine, sertraline, and fluoxetine have varying degrees of potency in inhibiting the hepatic cytochrome P450 (CYP) 2D6 enzyme. However, the time course for maximum inhibition to occur or for inhibition to dissipate when dosing is discontinued, requires clarification. In an open label, parallel group study of 45 healthy volunteers, the time course of CYP2D6 inhibition of the above SSRIs was evaluated. Subjects were randomized to receive paroxetine at 20 mg/day for 10 days; sertraline at 50 mg/day for 3 days, followed by sertraline at 100 mg/day for 10 days; or fluoxetine at 20 mg/day for 28 days. CYP2D6 activity was assessed using the dextromethorphan metabolic ratio (DMR) on antidepressant days 5 and 10 for sertraline and paroxetine and at weekly intervals for fluoxetine. Following SSRI discontinuation, calculation of a CYP2D6 inhibition half-life (t½inh) revealed the time course of fluoxetine inhibition (t½inh = 7.0 ± 1.5 days) to be significantly longer than either paroxetine (t½inh = 2.9 ± 1.9) or sertraline (t½inh = 3.0 ± 3.0) (p < 0.01), but the latter were not significantly different from each other (p > 0.05). Time for the extrapolated DMR versus time loglinear plots to return to baseline was significantly different between fluoxetine (63.2 ± 5.6 days) and both paroxetine (20.3 ± 6.4 days) and sertraline (25.0 ± 11.0 days) (p < 0.01), making the rank order (from longest to shortest) of time for CYP2D6 inhibition to dissipate: fluoxetine > sertraline ≥ paroxetine. Differences between mean baseline DMR values and measured values obtained after drug discontinuation for each drug group became nonsignificant on discontinuation day 5 for both paroxetine and sertraline and on discontinuation day 42 for fluoxetine. These data define the time course of a persistent effect that fluoxetine, sertraline, and paroxetine have on CYP2D6 following drug discontinuation and should be considered when initiating therapy with a CYP2D6 substrate.

Use of dexamethasone suppression test in clinical psychiatry.

The dexamethasone suppression test (DST) has been used in clinical medicine to evaluate overactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Consistent evidence has linked a specific dysfunction of the HPA axis to depressive illness. This article will review the physiology of the HPA axis and the method of the DST. After a critical review of the studies using the DST in psychiatric patients, the authors conclude that the overnight low dose DST can be a useful tool for the practitioner involved in the diagnosis and treatment of psychiatric illness.

Plasma measures of beta-endorphin/beta-lipotropin-like immunoreactivity in chronic pain syndrome and psychiatric subjects

This study compared basal concentrations of plasma beta-endorphin/beta-lipotropin-like immunoreactivity and dexamethasone suppression of cortisol in seven chronic pain patients, seven psychiatric disorder patients, and seven normal volunteers. Pain patients and psychiatric patients showed significantly higher basal concentrations of beta-endorphin/beta-lipotropin-like immunoreactivity compared to normal volunteers. Pain patients also had significantly higher beta-endorphin/beta-lipotropin-like immunoreactivity than psychiatric patients, even though there was no significant difference in severity of depressive symptomatology as assessed by Beck and Hamilton scores. Resistance to dexamethasone occurred in 57% of pain patients. These results may indicate that biological markers for depression occur in populations of chronic pain patients, or may reflect levels of central nervous system arousal in response to stress, pain, or nonaffective phenomena.

Adrenergic-cholinergic balance and the treatment of affective disorders

Centrally acting cholinomimetic drugs cause anergia, behavioral inhibition and depression. Centrally acting cholinomimetic drugs have antimanic properties. Combinations of acetylcholine precursors and centrally active cholinomimetic agents may cause augmented muscarinic effects, as may a combination of an antiadrenergic and cholinomimetic drugs. Centrally active anticholinergic agents may exert antidepressant effects. Affective disorder patients may show hyperreactivity to cholinomimetic agents, a phenomena which may have diagnostic significance.

Central cholinergic stimulation causes adrenal epinephrine release.

Cholinergic drugs administered into the cerebral ventricles of animals selectively stimulate the adrenal medulla. However, the effects of central cholinergic stimulation on the sympathoadrenal system have not been studied in man. We stimulated central cholinergic activity in man by administering the cholinesterase inhibitor physostigmine to subjects pretreated with peripheral cholinergic blocking agents. A dose of 0.022 mg/kg physostigmine dramatically increased plasma epinephrine levels and slightly increased norepinephrine levels, which is consistent with selective adrenomedullary stimulation. A smaller dose of physostigmine increased epinephrine but did not alter norepinephrine levels. Subjects had increased pulse rates and blood pressures, and felt anxious while they had high plasma epinephrine levels.

Neurochemical mechanisms in the affective disorders and neuroendocrine correlates.

This symposium offers the practicing clinician a general overview of ongoing research strategies exploring possible functional alterations in neurotransmitters, neuroreceptors, and regulatory neuropeptides in subjects with major affective disorders. Such alterations, if demonstrable, might provide new mechanistic insights into the pathophysiology of these illnesses and suggest novel therapeutic approaches to their pharmacological management. Rather than attempting to describe all neurobiological research strategies, we have selectively focused on strategies using specific pharmacological challenges attempting to perturb discrete central nervous system neurotransmitter pathways while recording the behavioral and neuroendocrine correlates of such manipulations. This introductory manuscript will describe the advantages as well as the limitations of such strategies and, in addition, will attempt to provide a general overview of neuroanatomical, neurochemical, and neuroendocrine mechanisms relevant to a conceptual understanding of the putative psychiatric relevance of such strategies.

Basal and post-dexamethasone cortisol and prolactin concentrations in depressed and non-depressed patients with chronic pain syndromes

&NA; To assess the behavior of two putative neuroendocrine markers of depression in chronic pain, the authors determined plasma cortisol and prolactin concentrations before and after dexamethasone in 52 hospitalized male chronic pain patients. Their psychiatric diagnoses by Research Diagnostic Criteria (RDC) were: major depression (N = 24; 44.2%), minor depression (N = 10; 19.2%), another RDC diagnosis (N = 7; 13.5%) and not mentally ill (N = 12; 21.6%). Failure to suppress cortisol after dexamethasone (a positive DST) occurred in 43.5% of those with major depression, 20% of those with minor depression, 42.8% of those with other psychiatric diagnoses and in 8.3% of patients without a psychiatric disorder. The frequency of non‐suppression was significantly different only for patients with major depression compared to those without diagnosable psychiatric disorder. Mean basal cortisol concentrations at 08.00, 16.00 and 23.00 h did not differ among psychiatric diagnostic groups of pain patients, or between these groups and healthy volunteers. Levels of prolactin, but not cortisol, were significantly correlated with the severity of mood disturbances. These findings suggest strategies using multiple endocrine markers to distinguish pain from depression should be explored.

Indications and Guidelines for Plasma Tricyclic Antidepressant Concentration Monitoring

Some tricyclic antidepressants appear to have critical ranges of plasma tricyclic antidepressant concentrations necessary for optimal clinical efficacy. For any given dose of tricyclic medication, there are marked interindividual variations in steady-state tricyclic concentrations. Furthermore, plasma tricyclic concentrations may be influenced by factors such as weight, diet, smoking status, differences in bioequivalence among manufacturers, and the addition or withdrawal of concurrent medications. There has been considerable controversy in the literature about the clinical utility of plasma tricyclic level monitoring. These authors believe that, at present, routine plasma level monitoring probably is not warranted, but that there are a variety of instances where plasma tricyclic concentration determinations may be clinically useful. The authors review methodological issues in plasma tricyclic concentration determinations and suggest guidelines for when such determinations may be clinically appropriate.

Atenolol treatment of late luteal phase dysphoric disorder

Activation of the renin-angiotensin-aldosterone system has been hypothesized as a potential pathophysiological factor in premenstrual tension syndrome (PMS). Atenolol is a predominate beta 1-blocker which can decrease plasma renin activity and inhibit the urinary excretion of aldosterone. Sixteen women meeting provisional diagnoses of late luteal phase dysphoric disorder were treated for symptoms of PMS with atenolol (50 mg once daily) in a randomized placebo-crossover double-blind design. The data indicated significant improvements on the irritability, vigor, elation, and friendliness scores in response to atenolol compared to placebo. Significant changes were not found for several other ratings scales, indicating that atenolol improved only selected symptoms in the group as a whole. However, the women who had premenstrual tension symptoms for more than 5 years (n = 8) were improved on most of the rating scales. Atenolol decreased premenstrual plasma aldosterone to a limited extent. There was also a trend in the data toward higher luteal progesterone levels during the month subjects took atenolol. Plasma renin activity and aldosterone correlated with estrogen and progesterone levels during the placebo month but not during the active month.